Amyloid fibers are remarkably stable, self-assembled filaments that can be formed from virtually any protein. As polypeptides are readily mutated and/or derivatized, these properties make amyloid an attractive system for the development of biological nano-structures. Fiber formation involves the sampling of heterogeneous intermediate species, both conformational and oligomeric, as a central part of the pathway for assembly. Importantly, it is these intermediates, not fibers themselves that are associated with cytotoxicity in diseases such as Alzheimer's. [unreadable] [unreadable] Promising insights into the molecular basis of fibrillization have been deduced from the interactions of amyloidogenic proteins with interfaces, particularly lipid bilayers. These stabilize and organize structural intermediates thereby catalyzing fiber formation. It is also these interactions that are implicated as causal to cell death in amyloid diseases. The mechanism of the latter involves disruption of membranes and elimination of the ion gradients required for normal cellular function. Despite great interest in membrane bound amyloid intermediates, and their obvious relevance to pathology, their molecular characterization has been elusive due to their heterogeneous and transient nature. [unreadable] [unreadable] Single molecule fluorescence measurements are uniquely capable of quantification of heterogeneous and dynamic molecular populations. These will be developed and applied to the study of interactions of islet amyloid polypeptide (IAPP) with synthetic lipid vesicles. Two areas are specifically addressed: (1) characterization of the mechanism of membrane integrity loss induced by IAPP and (2) determination of IAPP states and dynamics associated with membrane disruption. The results of these investigations will provide a description of the molecular species involved in membrane permeabilization, and give insight into the mechanism of fiber assembly. Such understanding is critical to developing processes for manipulation and control of fiber assembly, will provide new tools for studying the behavior of membrane proteins and amyloid intermediates both in vitro and in vivo, and finally, will provide a basis for identifying novel targets suitable for the development of therapeutics. Understanding the processes by which proteins form pathological amyloid fibers requires a detailed description of the heterogeneous molecular species populated during fibrillization. This includes the membrane-associated structures that are implicated as causal agents in cell death in amyloid diseases. The aim of this work is to develop single molecule methods for studying interactions between the amyloidogenic protein, islet amyloid polypeptide, and lipid bilayers with a view towards identifying novel targets suitable for the development of therapeutics. [unreadable] [unreadable] [unreadable]